Most bone and cartilage structures of the jaw and throat are derived from cephalic neural crest cells. These cells, arising from the hindbrain, migrate to the pharyngeal arches, where they undergo a proliferation and differentiation program culminating in the formation of craniofacial structures. While numerous signaling cascades regulate this developmental program, the effectors of these cascades are poorly defined. This Independent Scientist Award application requests salary support for the candidate to elucidate the downstream effectors of endothelin-A receptor signaling that control development of cephalic neural crest cells and their derivatives. The candidate will use a variety of techniques to accomplish this aim, including analysis of genomic changes using custom cDNA microarrays and analysis of proteomic changes using 2D-gel electrophoresis and mass spectroscopy. Career goals of the candidate are centered on developing an active research laboratory dedicated to understanding the molecular and cellular basis of normal and abnormal craniofacial development. This lab will serve the additional goal of training pre- and post-doctoral students in craniofacial research. An ISA will enhance the candidate's development as an independent investigator by enabling specific expansion of expertise and research activities. Immediate plans include traveling to an external laboratory to develop expertise in the production and analysis of large-scale custom cDNA microarrays, as well as learning modern techniques in protein profiling and identification at the Core Proteomics Laboratory and the Biomolecular Mass Spectroscopy Core Laboratory, both at the University of Louisville. To take full advantage of the array and proteomic data, the candidate will also attend a bioinformatics course designed to enable researchers to write programs to manage genomic and proteomic research data. The Institution's development plans include: provision of significant start-up funds; guaranteed salary support beyond the period of time requested for K02 support; permission for the candidate to spend essentially full-time conducting research: minimal departmental duties; funds to travel to laboratories as outlined in the candidate's plans; provision of funds to hire a post-doctoral fellow to contribute to the growing research program in the candidate's laboratory: participation in monthly inter- and intra-departmental discussion groups designed to facilitate the development of the candidate's research program. The research environment offers excellent opportunities for scientific interactions that foster scientific growth and development. Many senior investigators direct active research programs at the University of Louisville, offering many potential interactions. Importantly, the candidate's chairman is a well-established investigator studying the molecular and cellular basis of facial birth defects. Both his personal interaction as well as his continuing efforts to recruit individuals with active research programs in the areas of craniofacial development and genetics underscores the commitment to build a strong research group, further helping the candidate build his own research program.